Process for producing 2-carbalkoxyaminobenzimidazoles



United States Patent 3,480,642 PROCESS FOR PRODUCING 2-CARBALKOXY-AMINOBENZIMIDAZOLES Robert John Stedman, Paoli, Pa., assignor to SmithKline & French Laboratories, Philadelphia, Pa., a corporation ofPennsylvania No Drawing. Filed Mar. 22, 1967, Ser. No. 625,009 Int. Cl.C07d 49/38 US. Cl. 260309.2 10 Claims ABSTRACT OF THE DISCLOSURE Aprocess for selectively acylating 2-aminobenzimidazoles in the2-position, by heating the reaction product of Z-aminobenzimidazole andan alkyl haloformate in the presence of a suitable non-hydroxylicsolvent. The resulting Z-carboalkoxyaminobenzimidazoles are generallyknown compounds, which have anthelmintic activity.

This invention relates to a process for preparingcarbalkoxyaminobenzimidazoles. In particular, this invention relates toa chemical process for the preparation of 2-carbalkoxyaminobenzimidazoles having a high degree of anthelminticactivity.

The high incidence of helminth infections throughout many areas of theworld motivates the search for an effective, nontoxic, inexpensive, andreadily obtainable anthelmintic. 2 carbalkoxyaminobenzimidazoles havebeen found to possess considerable activity against pin- Worm, hookworm,and whipworm infections and offer considerable promise in fulfilling theabove-mentioned criteria for an anthelmintic agent.

Prior methods of preparation of 2-carbalkoxyaminobenzimidazoles includecondensation of o-phenylenediamine with the reaction product ofS-methylthiourea and an alkyl chloroformate.

The present process is advantageous in relation to the prior artprocesses due to its ease of execution and lack of evolution ofodiferous mercaptans. It also avoids the problem of the preparation ofan undesired isomeric compound, often encountered in. the directreaction of 2-aminobenzimidazole with an alkyl chloroformate. Further,it requires the use of only one molecular equivalent of acylatiug agent.

The present process provides a convenient and relatively inexpensivemethod for the preparation of the anthelminticZ-carbalkoxyaminobenzimidazoles.

The process of the invention is represented graphically as follows:

N H Y I ll R0 CHalo NH2 A -NHCO OR i N N 1 H Y C 0 OR Y II III In theabove process,. acylation of a ring-substituted, or unsubstituted,2-aminobenzimidazole with an alkyl haloformate under cold conditions,give the l-carbalkoxy derivative of the starting compound. By heatingthis relCC action product from 5 minutes to two days at 50100 C., 1n thepresence of a suitable nonhydroxylic solvent, preferably pyridine, thel-substituted compound is converted to its Z-carbalkoxyamino isomer.Other useful solvents are dimethyl formamide and acetonitrile.

The 2-aminobenzimidazole reactant can have any of a number ofconventional substituents, preferably one or two, on the benzene ring(represented by X and Y in the Formula I above) which are inert to thecondensation reaction, such as alkyl straight or branched containingfrom one to nine carbon atoms, alkaryl preferably benzyl, arylpreferably phenyl, dialkylamino, halo preferably chloro, alkoxy straightor branched containing from one to nine carbon atotrns, trifluoromethyl,alkylthio, cyano, carbalkoxy, the alkyl moieties not specificallydefined having from one to four carbons.

The resulting Z-carbalkoxyaminobenzimidazoles bear these substituents atthe corresponding position of the benzene ring. The nature of the novelreaction is such that it is generally applicable toZ-aminobenzimidazoles, regardless of the substituents which may appearon the benzene ring.

The alkyl haloformate can be a chloroformate or a bromoformate, thechloroformate being preferred for reasons of availability and cost. Theside alkyl group R can have from one to about twelve carbon atoms,therein, the choice of alkyl group being dependent upon the particularalkyl ester product desired. The term alkyl is also intended to refer tocycloalkyl groups of 3 to 6 carbon atoms, and alkylcycloalkyl groups of4 to 6 carbon atoms.

The starting materials of Formula I above are either known or areprepared by methods known to the art.

The compounds of Formula I where X is 5-alkl, -aryl or -aralkyl and Y ishydrogen may be prepared starting with the appropriate para-substitutedaniline, which is first acetylated with acetic anhydride to protect theamino group, forming p-substituted acetanilide. The anilide is nitratedin the presence of acetic or sulfuric acid to form 2-nitro-4-alkylanilide, e.g., which is reduced with tin chloride to give2-amino-4-alkylanilide. Hydrolysis liberates the amino group to give4-alkyl substituted o-phenylenediamine. Treatment of the latter withbromocyanogen forms the S-alkyl substituted Z-aminobenzimidazole.Similarly, are the aryl or aralkyl substituted congeners prepared.

The compounds of Formula I wherein both of X and Y are lower alkyl maybe prepared starting with the apprOpriate dialkyl benzene. For example,ortho-xylene is nitrated in the presence of acetic acid to form the 4-nitro-l,2-dimethyl benzene. This intermediate is reduced with tinchloride to give the corresponding 4-amino compound, followed bynitration in mineral acid medium with amyl nitrate to give a5-nitro-4-amino-1,2-dimethyl benzene. This latter intermediate is againreduced with tin chloride to yield a 4,5-dimethyl o-phenylenediamine.The diamine intermediate is converted by the afore-discussedbromocyanogenation to the appropriate dimethyl substitutedZ-aminobenzimidazole.

The compounds of Formula I in which X is dialkylamino and Y is hydrogen,can be prepared starting with a dialkylaminobenzene, and following theabove-described sequence of steps to yield the dialkylamino substituted2-aminobenzimidazole.

The compounds of Formula I wherein X is halo and Y is hydrogen, areprepared starting with a p-haloaniline, such as p-chloroaniline. Thehalo compound is first acetylated with acetic anhydride to protect theamino group forming p-chloroacetanilide. The anilide is nitrated in thepresence of acetic or sulfuric acid to form 2-nitro-4-chloroacetanilide,which is reduced catalytically, such as with tin chloride, to give thecorresponding 2-amino-4-ch1oroacetani1ide. This amino compound ishydrolyzed to produce 4-chloro-0-phenylenediamine. The diamine isconverted to the corresponding S-chloro-Z- amino-benzimidazole by theafore-discussed bromocyanogenation.

The compounds of Formula I wherein X and Y are Y is hydrogen areprepared starting with 4-hydroxyacetanilide. The anilide is treated withthe appropriate alkyl bromide and an alkali metal hydroxide, to yieldthe corresponding o-dialkoxybenzene. The substituted procedure ofBuu-Hoi et al., J. Chem. Soc., 1955, 1573. The substituted compound isnitrated with red fuming nitric acid, while suspended in glacial aceticacid and acetic anhydride at about C. The resultingo-nitro-palkoxyacetanilide is collected, and is recrystallized frommethanol. This disubstituted acetanilide is then deacylated by refluxingwith an alkali metal hydroxide in ethanol, with the disubstitutedaniline being recovered from acidified water. The disubstituted anilineis then hydrogenated at 50-80 p.s.i. in benzene, with removal of thesol-- vent by distillation, yielding the corresponding diamine. Thisdiamine intermediate is converted by either of the afore discussedbromocyanogenation to the appropriate lower alkoxy substituted2-aminobenzimidazole.

The compounds of Formula I wherein X and Y are alkoxy are preparedstarting with o-dihydroxybenzene. The benzene is treated with theappropriate alkyl bromide, and an alkali metal hydroxide in ethanol, toyield the corresponding 'o-dialkoxybenzene. The substituted compound isnitrated with nitric acid while suspended in acetic acid, to yield1,2-dialkoxy-4,S-dinitrobenzene (J. Proc. Roy. Soc., N. S. Wales, 71,103-11 (1938)), followed by hydrogenation to give the correspondingsubstituted diamine. The diamine is converted, as previously described,to a 4,5 dialkoxy-substituted 2- aminobenzimidazole.

All of the foregoing classes of substituted 2-arninobenzimidazole arethen subjected to the process of the present invention.

The prior art discloses a process for the direct acyla tion of2-aminobenzimidazole with alkylchloroformate allegedly to give2-carbalkoxyaminobenzimidazole (M. Ridi and S. Checchi, Ann. Chim,Rome), 28-38 (1954). I have demonstrated that following the teaching ofRidi et al, the only product isolable, under normal conditions, is a1-carbalkoxyaminobenzimidazole. Consequently, when selective 2-acylationis sought, the prior art process is inoperative. Only the here disclosedreaction conditions gives the preferred 2-isomer.

The following examples are intended to illustrate the process of theinvention, 'but are not to be considered as limiting the scope thereof.Certain variations in the conditions and reactants of the presentprocess may be made which are obvious to one skilled in the art oforganic chemistry, 'but to the extent that they are within the spirit ofthe invention, they are within the scope thereof.

EXAMPLE 1 Attempted preparation of 2-carboethoxyaminobenzimidazole Theprocedure reported by Ridi et al., Chemical Abstracts, vol. 49: 4658 59(1955), was followed to determine what product was the result of theteaching.

To a cooled solution (0 C.) of 3 g. of Z-aminobenzimidazole (EastmanChemicals Company), in ml. of water is added slowly 2.4 g. ofethylchloroformate. Eight ml. of 10% sodium hydroxide were addedconcurrently, the resulting mixture having a basic pH when all reactantswere added. The mixture was stirred for about minutes with cooling. ThepH was then adjusted to 7.5 with 3 N HCl, precipitating a solid, whichwas collected, washed with 25 ml. of 95% ethanol, and air dried on aporous plate.

The mother liquor was refrigerated and a second crop was precipitatedtherefrom, collected, and washed with water, both crops yielding a totalof 2.574 g. of product. The product had an M.P. of C. after which itresolidified. It then failed to remelt below 300 C-.-

The collected material was submitted for an infra-red spectrum which wascompared with the spectrum for an authentic sample of1-carboethoxyaminobenzimidazole. The spectra were identical. Additionalsamples were submitted for thin layer chromatography and compared with achromatogram for an authentic sample of 2-carboethoxyaminobenzimidazole.This chromatogram indicated that only a trace of the 2-isomer waspresent.

It was concluded, therefore, that the prior art method yieldedsubstantially only l-carboalkoxyaminobenzimidazole.

EXAMPLE 2 Preparation of Z-carboethoxyaminobenzimidazole To a cooledsolution (0 C.) of 5 g. of 2-amin0benzimidazole in 30 ml. of drypyridine is slowly added 4.06 g. of ethyl chloroformate, with a solidsuspension forming during the addition. The mixture is stirred for about10 minutes with cooling. Upon the addition of about 2 volumes of water,a white solid precipitates, which is collected, washed with cold water,and oven dried.

The structure of this product is confirmed by elemental analysis andspectral data as being l-carboethoxyaminobenzimidazole.

1-carboethoxybenzimidazole (4 g.) is dispersed in 40 ml. of dry pyridineand is refluxed for 2 hours. Upon the addition of 3 volumes of water, asolid precipitates, which is collected, washed liberally with water, andair dried on a porous plate.

The crude product is suspended in 50 ml. of 50% aqueous ethanol, then10% aqueous sodium hydroxide is added until strongly basic. Theinsoluble material is removed by filtration, and the filtrate isneutralized with 3 N hydrochloric acid to a pH of about 7.5. A whitesolid precipitate is collected, washed and desiccated, M.P. 326 C. (d.).

The structure of the product is confirmed by elemental analysis andspectral data as Z-carboethoxyaminobenzimidazole.

EXAMPLE 3 Preparation of 5-n-butyl-2-carbomethoxyaminobenzimidazole Theavailable intermediate p,n-butylaniline is treated with acetic anhydridein hexane solution, yielding 4-nbutylacetanilide. The acetanilide isnitrated with fuming nitric acid in the presence of acetic anhydride andglacial acetic acid to produce 4-n-butyl-Z-nitroacetanilide. Thepreceding Z-nitro compound is refluxed in 12 N hydrochloric acid todeacetylate the amino group. The resulting 2-nitroaniline derivative isreduced with stannous chloride in 6 N hydrochloric acid to yield4-n-butyl-o-phenylenediamine. The dihydrochloride salt of the abovesubstituted phenylenediamine is treated in a water solution withbromocyanogen to yield S-n-butyl-Z-aminobenzimidazole.

To a cooled solution of 3 g. of 5-n-butyl-2-aminobenzimidazole in 18 ml.of dry pyridine, is slowly added 1.49 g. of methyl chloroformate, whilestirring. The mix ture is stirred for about 10 minutes with cooling,then refluxed for about 15 minutes, and finally immediately recooled.Upon addition of one volume of water (18 ml.), 9. white solidprecipitates, which is collected, washed with cold water, and is ovendried.

The crude product is then suspended in 50% aqueous ethanol, with 3 Nhydrochloric acid being added until the pH is acid, and stirred forseveral minutes. The insoluble material is filtered off, and thefiltrate is basified to pH 7.5 by the addition of 10% sodium hydroxideaqueous solution, which precipitates a white solid product.

The product is collected, washed with 50% aqueous ethanol, desiccatedover P and is oven dried, MP. 218- 222 C. (d.).

The structure is confirmed by elemental analysis and Spectral data.

EXAMPLE 4 1 When the following substituted Z-aminobenzimidazoles aresubstituted for the 5-n-butyl-2-aminobenzimidazole in the procedure ofExample 3, the corresponding listed products are obtained.

Starting material Product 5-eh1oro-2-aminob enzimidazole5-ch1oro-2-carbomethoxyaminobenzimidazole.5-ethoxy-Zaminobenzimidazole....5-ethoxy-2-carbomethoxyaminobenzimidazole.fi-methoxy-ibaminobenzimidazoleS-methoxy-Zcarbomethoxyarninobenzimidazole.5-propoxy-Z-aminobenzimidazole5-propoxy-Z-carbomethoxyaminobenzimidazole.5-isopropoxy-2-aminobenzimidazo1e5-isopropoxy-2-carbomethoxyaminobenzimida-zole.5-butoxy-2-aminobenzimidzaole 5-butoxy-2-earbomethoxyaminobenzimidazole.5-amy1oxy-2-arninobenzimidazole 5amyloxy-2-carbornethoxyaminobenzimidazole. 5,6-dibutoxy-2-aminobenzirnidazole5,6-dibutoxy-Z-carbomethoxyaminobenzimida-zole.5-methyl-2-aminobenzimidazole 5-methyl-2-carbomethoxyaminobenzimidazole.5-n-propyl-2-aminobenzimidazole.5-n-propyl-2carbomethoxyaminobenzimidazole. fi n-amyl-flaminobenzimidazole--. 5-namyl-2-carbomethoxyarninobenzimidazole.fi-n-hexyLZ-aminobenzimidazole 5-n-hexyl-2-carbomethoxyaminobenzimidazole.

5,6-dimethyl-2-aminobenzimidazole5,6-(1imethyl-2-carbomethoxyamino-benzimidazole.

5-carbomethoxy-Z-carboniethoxy- :12 e. amino-benzimidazole.

5-dimethylamino-2arninobenzhnid- E-dirnethylamino-2-carbomethoxyazole.aminobenzimidazole.

dearbomethoxy-Z-arniuobenzimid- I claim:

1. A process for preparing a 2-carboalkoxyaminobenzirnidazole comprisingtreating a Z-aminobenzimidazole with an alkyl haloformate to form a1-carbalkoxy-2- aminobenzimidazole, and then heating the l-carbalkoxycompound in a non-hydroxylic solvent selected from one of pyridine,dimethyl formamide, and acetonitrile sufiiciently long in thetemperature range of 50 to 100 C. to form the correspondingZ-carbalkoxyaminobenzimidazole.

2. A process for preparing a Z-carboalkoxyaminobenzimidazole whichcomprises treating a Z-aminobenzimidazole of the formula:

\ NHE where X and Y are hydrogen, alkyl straight or branched from one tonine carbon atoms, phenyl, benzyl, chloro, bromo, alkoxy straight orbranched from one to nine carbon atoms, alkylthio, dialkylamino,carballgoxy, trifluorgmethyl, or cyano, the alkyl moieties having fromone to four carbon atoms, with Hal-COOR, where Hal is halo and R isalkyl from one to six carbon atoms or cycloalkyl from three to twelvecarbon atoms, to form a lcarbalkoxy-Z-aminobenzimidazole, and thenheating the l-carbalkoxy compound in a non-hydroxylic solvent selectedfrom one of pyridine, dimethyl formamide, and acetonitrile sufiicientlylong in a temperature range of 50 to C. to form a2-carbalkoxyaminobenzimidazole of the formula:

NHCOOR X l --N H Y where X, Y, and R are as defined above.

3. A process according to claim 1, in which the solvent is pyridine.

4. A process according to claim 1, in which the heating is carried outin the range of from 50 to 100 C., and from 5 minutes to two days.

5. A process according to claim 2, wherein X is alkyl and Y is hydrogen.

6. A process according to claim 2, wherein X is alkoxy and Y ishydrogen.

7. A process according to claim 2, wherein X is chloro and Y ishydrogen.

8. A process according to claim 2, wherein both X and Y are alkyl.

9. A process according to claim 2, wherein both X and Y are alkoxy.

10. A process according to claim 2, wherein X is n-butyl and Y ishydrogen.

References Cited UNITED STATES PATENTS 2,933,502 4/1960 Klopping260-3092 2,933,504 4/1960 Klopping 260309.2 3,010,968 11/1961 Loux260-3092 OTHER REFERENCES Ridi et al., Chem. Abst., vol. 49, column4658-9 (1955).

Ridi et al., Ann. Chim. (Rome), vol. 44, pages 28-38 (1954).

HENRY R. JILES, Primary Examiner NATALIE TROUSOF, Assistant Examiner US.01. X.R.

